Antisense oligonucleotides and their use for treating Pendred syndrome
an anti-sense oligonucleotide and pendred syndrome technology, applied in the field of anti-sense oligonucleotides and their use for treating pendred syndrome, can solve the problems of no drugs available to treat pendred syndrome, no treatment options directed, and leakage of cerebro-spinal fluid, so as to prevent or reduce exon 8 skipping
Active Publication Date: 2022-04-26
ASOCURA PHARM SUZHOU CO LTD
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Benefits of technology
The ASOs effectively increase exon 8 inclusion in treated cells, potentially restoring functional pendrin protein production and improving hearing outcomes in subjects with Pendred syndrome.
Problems solved by technology
The implantation process may cause a leak of cerebro-spinal fluid in patients with a Mondini cochlea.
Currently, there are no drugs available to treat Pendred syndrome, and no treatment options directed to the underlying genetic cause of Pendred syndrome.
This may result in a non-functional polypeptide sequence or a premature stop codon.
The splicing process is further complicated by alternative splicing, where the same pre-mRNA sequence can be spliced into different exon combinations to form multiple mRNA sequences.
Because the splicing process is entirely dependent on spliceosome recognition sites, 5′ and 3′ splice sites, and the branch site, a mutation in any one of these sites can disrupt the splicing process.
The incorrect removal of exon 8 from the final mRNA transcript causes a disruption of the reading frame during translation, resulting in a truncated and dysfunctional pendrin peptide.
Method used
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[0106]The following Example serves to more fully describe the invention. It is meant for illustrative purposes and is not meant to limit the invention in any way.
Materials and Methods
[0107]ASOs modified with 2′-O-methoxyethyl (MOE) ribose, a phosphorothioate (PS) backbone, and containing 5-methylcytosines in place of all cytosines were purchased from Biosyntech (Suzhou, China) and dissolved in DEPC-treated water with a stock solution at 20 μM. A human SLC26A4 minigene c.919-2A>G mutant (1212 bp) comprising of the 153-nt exon 7, the 100-nt intron 7, the 83-nt exon 8, a shortened 701-nt intron 8 (382+6+313), the 148-nt exon 9, and the first 27-nt sequence of intron 9, was constructed in pCI-neo vector via two steps. First, a 718-nt genomic DNA fragment (from exon 7 to the first 382-bp sequence of intron 8) was cloned in the vector at restriction sites XhoI and XbaI and then a 488-bp genomic DNA fragment (from the last 313-bp sequence of intron 8 to the first 27-nt sequence of intron 9...
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Abstract
The present disclosure relates to the field of medicine. In particular, it relates to novel antisense oligonucleotides that prevent or reduce exon 8 skipping in the SLC26A4 gene during pre-mRNA splicing, and their use in the treatment of Pendred Syndrome.
Description
CROSS REFERENCES TO RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Patent Application No. 62 / 975,337, filed Feb. 12, 2020, which is hereby incorporated by reference in its entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Feb. 10, 2021, is named 13365_0018-00304_SL.txt and is 16,709 bytes in size.FIELD OF THE DISCLOSURE[0003]The present invention relates to novel antisense oligonucleotides (“ASOs”) that prevent or reduce exon skipping during pre-mRNA splicing, pharmaceutical compositions containing such ASOs, and their use.BACKGROUND OF THE DISCLOSURE[0004]Pendred syndrome is a sensorineural hearing loss disorder. It is one of the most frequent causes of syndromic deafness, accounting for about 4-10% of all hereditary deafness cases. Patients with Pendred syndrome have a malform...
Claims
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IPC IPC(8): C12N15/113
CPCC12N15/113C12N2310/11C12N2310/315C12N2310/321C12N2310/3341A61K31/7088C12N15/1138C12N2320/33C12N2310/322A61P27/16C12N2310/3525A61K48/005
Inventor HUA, YIMIN
Owner ASOCURA PHARM SUZHOU CO LTD